Glaucoma is a disease characterized by the elevation of intraocular pressure (IOP) due to various pathogenesis leads to damage and atrophy of the optic nerve resulting in the abnormal visual field, and thus visual acuity is gradually reduced. Since the optic nerve does not recover once atrophy occurs, glaucoma is a refractory disease in that not only vision is lost if glaucoma is untreated, but also the condition is only maintained even after successful treatment, and recovery cannot be expected. Furthermore, ocular hypertension, which may lead to development of glaucoma over a long time although in the absence of visual field defects, also has a similar risk.
Glaucoma is classified into three types: congenital (developmental) glaucoma, secondary glaucoma, and primary glaucoma. Patients with congenital (developmental) glaucoma are born with growth deficiency of the iridocorneal angle, and obstruction of the aqueous outflow causes this type of glaucoma. Secondary glaucoma arises as a result of inflammation or injury and is caused by such as uveitis or ocular trauma as well as hemorrhage due to diabetes, long-term use of steroid hormones for the treatment of other diseases, and the like. Primary glaucoma is a generic name of glaucomas of types with unclear causes and occurs most commonly of glaucomas, with a high incidence among middle aged and elderly persons. Primary glaucoma and secondary glaucoma are further subdivided into two types, open-angle glaucoma and angle-closure glaucoma, depending on the blockage of the aqueous outflow. While many patients develop normal tension glaucoma in the absence of elevated IOP, the primary aim of glaucoma treatment is to lower the IOP.
For the treatment of glaucoma, laser treatment (laser trabeculoplasty), surgical therapy (trabeculectomy or trabeculotomy), or the like is performed when IOP cannot be controlled with a drug or a patient with angle-closure glaucoma has an acute glaucoma attack, but drug therapy is used as the first line therapy.
Drugs used in the drug therapy of glaucoma include sympathetic nerve stimulants (nonselective stimulants such as epinephrine and α2 stimulants such as apraclonidine), sympathetic nerve blockers (β blockers such as timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol and α1 blockers such as bunazosin hydrochloride), parasympathetic nerve agonists (pilocarpine, etc.), carbonic anhydrase inhibitors (acetazolamide, etc.), prostaglandins (isopropyl unoprostone, latanoprost, travoprost, bimatoprost, etc.), and so forth.
Of these, bunazosin hydrochloride is a drug first developed as an agent for selectively blocking sympathetic nerve α1 receptors, unlike existing remedies for glaucoma. As its mechanism of action, bunazosin hydrochloride locally acts on the eyes by instillation and lowers IOP by promoting aqueous outflow from the uveoscleral outflow pathway (Non-patent Document 1).
Meanwhile, Rho kinase inhibitors have been found as candidate remedies for glaucoma based on a novel mechanism of action (Patent Documents 1 and 2). Rho kinase inhibitors lower IOP by promoting aqueous outflow from the trabecular outflow pathway (Non-patent Document 2), and it is further suggested that this action may be attributed to changes in the cytoskeleton of a trabecular meshwork cells (Non-patent Documents 2 and 3).
In the treatment of glaucoma and ocular hypertension, drugs having an ocular hypotensive action are used in combination to enhance the additive ocular hypotensive effects. For example, combination use of a prostaglandin and a sympathetic nerve blocker (Patent Document 3), or a combination of some drugs having an ocular hypotensive action (Patent Document 4), and the like have been reported. Furthermore, combination use of a Rho kinase inhibitor and a β blocker (Patent Document 5) and a remedy for glaucoma comprising a Rho kinase inhibitor and a prostaglandin in combination (Patent Document 6) have also been reported.
However, the above-mentioned known remedies and therapies for glaucoma and ocular hypertension are far from satisfactory in view of the potency of the ocular hypotensive effect and the duration of action. In particular, it is more difficult to lower normal IOP in patients with normal tension glaucoma rather than lower elevated IOP. The above-mentioned existing drugs and combinations thereof have limitations in the treatment of normal tension glaucoma, and enhancement of the ocular hypotensive action is needed in the clinical setting.
Under such circumstances, there has been no report on glaucoma treatment using a Rho kinase inhibitor and a selective sympathetic nerve α1 receptor blocking agent in combination, and there has been no description about the cooperative effect of such a combination.    [Patent Document 1] WO00/09162    [Patent Document 2] JP-A-11-349482    [Patent Document 3] Japanese Patent No. 2726672    [Patent Document 4] WO02/38158    [Patent Document 5] JP-A-2004-182723    [Patent Document 6] JP-A-2004-107335    [Non-patent Document 1] Journal of Japanese Ophthalmological Society, 94(8), 762-768 (1990)    [Non-patent Document 2] IOVS, 42(1), 137-144 (2001)    [Non-patent Document 3] IOVS, 42(5), 1029-1037 (2001)